The etiology of Parkinson?s disease (PD) is currently unknown and treatment is unable to halt disease progression. Microglia, the innate immune cells of the brain, are implicated in PD progression, but the mechanisms driving continuous and pathologically activated microglia are poorly understood. Environmental factors are associated with PD etiology and can chronically activate microglia to cause dopaminergic (DA)neuron damage. Microglial NADPH oxidase and reactive oxygen species may have a role in deleterious microglial activation, but how they regulate microglial function is largely unknown. Our overarching hypothesis is that environmental insult (MPTP/MPP+ and LPS) causes chronic neuroinflammation and progressive DA neuron damage through changes in microglial protein radical biochemistry. Beginning with the NF?? radical, we will test the specific hypothesis that LPS and MPTP/MPP+- induced NADPH oxidase activation causes microglial protein radicals that drive progressive neuroinflammation and DA neurotoxicity by: A) enhancing the production of neurotoxic pro- inflammatory factors (microglial priming); B) mediating the failure of microglia to resolve the pro- inflammatory response. Preliminary data indicate that microglia respond to MPP+-induced DA neuron-injury signals and LPS by changing their protein radical profile and increasing the cytosolic NF?? p50 radical. Thus, beginning with the NF?? radical, the specific aims are to: 1) identify the proinflammatory and priming characteristics of NADPH oxidase-derived protein radicals (NF?? p50 radical); 2) define the role of astrocyte-microglia interactions on NF?? p50 radical formation, neuroinflammation, and microglia-mediated DA neurotoxicity; 3) characterize the role of the NADPH-oxidase derived NF?? p50 radical in progressive DA neuron damage in vivo; 4) determine the neuroprotective and anti-inflammatory effect of inhibiting NF?? p50 radical formation and function. We expect to systematically demonstrate for the first time that environmental insult causes protein radicals in microglia that fuel progressive DA neurotoxicity and identify these markers of deleterious microglial activation (i.e. NF?? p50). These studies will define a new avenue of research in PD pathogenesis and the role of environmentally-induced oxidative stress in neurodegenerative disease. Finally, this work will provide valuable insight into the identification and timing of novel therapeutic targets capable of slowing PD progression.